1. Field of the Invention
The present invention relates generally to the fields of oncology and the pharmacotherapy of neoplastic disease. More specifically, the present invention relates to a method of depletion of methionine in plasma and solid tumors and uses thereof.
2. Description of the Related Art
Methionine (MET).sup.4 is essential for normal growth and development of mammals. This amino acid participates in: (1) protein synthesis (Tautt, et al., 1982); (2) numerous S-adenosylmethionine dependent transmethylation reactions (Stern et al., 1984); (3) the formation of polyamines spermidine and spermine (Pegg et al., 1984); (4) synthesis of cystathionine, cysteine and other metabolites of the transulfuration pathway; (5) the supply of homocysteine (HCY).sup.4, which is needed for metabolism of intracellular folates; and (6) the catabolism of choline (Finkelstein, 1990).
With very few exceptions, normal cells can use homocysteine in place of methionine to support all of the above reactions (Hoffman, 1990; Guo, et al., 1993). In contrast to normal cells, a large number of cultured tumor cells and about 25% of fresh human tumors grown in histocultures cannot effectively utilize homocysteine in place of methionine, and such cells or tumors are classified as methionine-dependent (Guo, et al., 1993a; Guo, et al., 1993b). There is substantial evidence that methionine dependence occurs more frequently in metastatic tumor cells (Breillout, et al., 1987; Breillout, et al., 1990; Liteplo, 1990.), although reversion of dependence is not necessarily linked to loss of metastatic potential (Vanhamme, 1989). The biochemical basis for methionine dependency is not yet fully understood. Methionine-dependent tumor cells appear to synthesize methionine from homocysteine by an active methionine synthase, but at levels not adequate to both sustain growth and meet their high transmethylation requirements (Judde, et al., 1989). The most likely biochemical defect leading to methionine dependency is thought to be related to the synthesis and availability of methylcobalamine, which is directly involved in the transfer of methyl groups from 5-methyltetrahydrofolate to homocysteine (Liteplo, et al., 1991; Fiskerstrand, et al., 1994).
The defect in homocysteine utilization has been extensively investigated in order to induce selective killing of tumors while sparing normal tissues. Lack of methionine results in a reversible blockage of rapidly proliferating tumor cells in the late S and G2 phases of the cell cycle (Stern, et al., 1986; Guo, et al., 1993a). In general, cells arrested in S, G2 or M are not only susceptible to spontaneous death, as compared to cells arrested in G1, but they are also supersensitive to various chemotherapeutic drugs, such as doxorubicin, which blocks and kills in G2 (Stern, et al., 1986). Methionine-depleting diets in combination with chemotherapy suppress metastasis of Yoshida sarcoma and rhabdomyosarcoma tumors in animals (Breillout, et al., 1987; Goseki, et al., 1992). Potentiation of many drugs, some of which act by damaging cellular DNA, indicates that methionine deprivation may compromise DNA repair ability in addition to causing premitotic cell cycle blocks and cell death in tumors.
Modulation of resistance of tumor cells to chemotherapy may encompass a large number of mechanisms including those involved in the processing of the agent (metabolism, conjugation, etc), its transport into or its elimination from the target cell, or the reversal or repair of the damage induced by such agents. One or more of these mechanisms may be compromised in tumors by methionine deprivation, thus selectively sensitizing tumor cells to chemotherapy. A systematic study of the modulation of such mechanisms by deprivation of methionine will allow the deployment of the full potential of methionine dependence phenotype in the treatment of several tumors.
The prior art is deficient in the lack of effective means of depleting the levels of methionine in plasma and treatment of methionine-dependent tumors. The present invention fulfills this longstanding need and desire in the art.